This invention relates to the field of hemostatic devices for controlling bleeding.
Uncontrolled bleeding can result in shock and death. In surgical patients and patients receiving anticoagulant medication, the problem of rapid blood loss arising from, for example, a hemorrhage of a blood vessel, body tissue, organ or bone can give rise to a life threatening situation.
Biodegradable devices for controlling bleeding are commercially available. However, many of these devices require the impregnation of protein agents such as thrombin or fibrinogen to be effective. Unfortunately, special storage conditions are required to preserve the hemostatic activity of these protein agents. For example, many of these devices must be stored under refrigeration conditions to maintain the bioactivity of the hemostatic devices into which the protein agents have been impregnated. Such requirements prohibit certain field applications of the device, where refrigeration facilities are unavailable. Another problem with certain commercially available hemostatic devices is their lack of flexibility in the dry state. Many hemostatic devices do not conform easily to the shape of the body surface to which it is applied. In addition, hemostatic devices which further include hemostatic agents, such as thrombin, typically require that the thrombin be reconstituted and added to the dry devices immediately before use to provide a flexible hemostatic device having sufficient hemostatic activity to control bleeding.
The invention provides a hemostatic collagen fiber which can be processed into a hemostatic fabric. The collagen fibers and hemostatic fabric of the invention are collectively referred to herein as xe2x80x9chemostatic devicesxe2x80x9d. The hemostatic devices of the invention solve the above-described and other problems of the prior art hemostatic fibers and fabrics. For example, the hemostatic devices of the invention do not require exogenously added protein agents to be effective. Accordingly, the hemostatic devices of the invention can withstand elevated temperatures and do not require refrigeration to retain hemostatic efficacy. In addition, the hemostatic fabrics of the invention are easy to use and mold easily to body contours. Accordingly, the hemostatic fabrics of the invention are particularly useful for treating the problematic hemorrhages of parenchymal organs, spine and brain.
According to one aspect of the invention, a hemostatic collagen fiber is provided. Hemostasis is a term of art which refers to cessation of bleeding. The collagen fiber contains collagen particles (preferably, collagen fibrils) which, preferably, have a hemostatic activity that is equivalent to the hemostatic activity of the collagen fibrils from which the fiber is formed. In the preferred embodiments, the fiber is prepared by a process which involves extruding a collagen slurry containing collagen fibrils into a dehydrating bath. An exemplary process is summarized below and described in detail in the Examples.
In one embodiment of the invention, the method for forming a collagen fiber of the invention involves suspending a plurality of collagen particles (preferably, collagen fibrils) in water to form a collagen slurry. The collagen fibrils have a bulk density sufficient to form a suspension in water. In general, the bulk density of the collagen fibrils is in the range of from about 1.5 to about 3.5 lbs/ft3 and, more preferably, from about 2 to about 3 lbs/ft3. The fibrils are suspended in water to obtain a collagen concentration in the range of about 3% to about 10% (weight/volume). Preferably, the collagen fibrils of the fiber have a hemostatic activity that is equivalent to the hemostatic activity of the collagen fibrils from which the fiber is formed. In the preferred embodiments, the collagen fibers are formed of collagen fibrils that have not been subjected to acid dissolution or other denaturing conditions.
According to the foregoing embodiment, the collagen slurry is introduced into a first dehydrating bath to at least partially dehydrate the collagen slurry and, thereby, form a collagen fiber. The collagen fiber, optionally, is introduced into a second dehydrating bath to further dehydrate the fiber. Exemplary dehydrating baths that can be independently selected for use as the first or second (if present) dehydrating baths include (1) an ammonia bath comprising from about 10% to about 30% ammonia in water; (2) an ammonia/acetone bath comprising from about 50% to about 70% ammonia in acetone; (3) an acetone bath; (4) an ethanol bath; (5) an isopropanol bath (containing about 70% isopropanol in water); and (6) a propylene glycol bath (containing about 30% to about 95% propylene glycol in water).
Preferably, the first dehydrating bath is an ammonia bath and the second dehydrating bath is an acetone bath.
According to yet another aspect of the invention, a collagen fiber prepared by the above-described process is provided. According to yet another aspect of the invention, a collagen fabric formed of the collagen fibers of the invention and methods of preparing the collagen fabrics are provided. Such fabrics are also referred to herein as xe2x80x9chemostatic fabricsxe2x80x9d of the invention.
The collagen fibers and hemostatic fabrics of the invention are referred to herein as xe2x80x9chemostatic devicesxe2x80x9d of the invention. Such hemostatic devices can be sterilized and packaged in a sterile package for pharmaceutical applications.
In certain embodiments, the hemostatic devices of the invention further include a hemostasis-promoting amount of at least one hemostatic agent. As used herein, a xe2x80x9chemostasis-promoting amountxe2x80x9d is the amount effective to accelerate clot formation at an interface between a surface (e.g., of a wound or lesion) and the hemostatic fabric. Exemplary hemostatic agents include a thrombin molecule, a fibrinogen molecule, a source of calcium ions, an RGD peptide, protamine sulfate, an epsilon amino caproic acid, and chitin. In the preferred embodiments, the hemostatic agent is thrombin. The hemostatic agents can be introduced into the hemostatic devices at any stage during the preparation of these devices.
In certain embodiments, the hemostatic devices of the invention further include a therapeutically effective amount of at least one therapeutic agent, such as agents which promote wound-healing and or reduce pain (e.g., vascular pain). Agents which promote wound-healing and/or reduce pain include anti-inflammatory agents (steroidal and non-steroidal) such as agents which inhibit leukocyte migration into the area of surgical injury, anti-histamines; agents which inhibit free radical formation; and bacteriostatic or bacteriocidal agents.
Various additives, optionally, can be incorporated into the hemostatic devices of the invention without adversely affecting the hemostatic activity of these devices. The term xe2x80x9cpharmaceutically-acceptable carrierxe2x80x9d as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human. The term xe2x80x9ccarrierxe2x80x9d denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being co-mingled with the collagen fibrils of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired hemostatic activity.
The hemostatic devices of the invention are useful for promoting hemostasis at a site of bleeding (e.g., reducing or eliminating bleeding from a wound). Accordingly, a further aspect of the invention involves a method for promoting hemostasis. In general, such methods of the invention involve manually pressing a hemostatic fabric formed of the collagen fibers of the invention against a surface of a wound or a surface of a lesion on an organ, such as a parenchymal organ (e.g., spleen, liver, lung or pancreas), the spine, or the brain, for a period of time until clotting has occurred at the interface between the hemostatic fabric and the surface.
According to yet another aspect of the invention, a collagen fiber is provided, wherein the collagen fibrils of the fiber have a hemostatic activity that is equivalent to the hemostatic activity of the collagen fibrils from which the fiber is formed. Hemostatic fabrics formed of such collagen fibers also are provided. Although not wishing to be bound to any particular theory or mechanism, it is believed that avoiding contact between the collagen and an acid solution and minimizing exposure of the collagen to a denaturing condition such as, e.g., excess mechanical shear, high temperature, or long water residence times, during the fiber- or fabric-forming process results in a greater retention of hemostatic activity by the collagen.
A number of embodiments of the invention are summarized above. However, it should be understood that the various limitations presented in each embodiment are not mutually exclusive and, accordingly, the limitations can be combined to obtain further aspects of the invention.